Epilepsy is a neurological condition characterized by recurrent, unprovoked seizures (Blume et al., Epilepsia. 2001; 42:1212-1218). These seizures are transient signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain (Fisher et al., Epilepsia 46 (4): 470-2). Epilepsy should not be understood as a single disorder, but rather as a group of syndromes with vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain. It is one of the most common serious neurological disorders in the United States and often requires long-term management. Each year 150000 people in the United States are newly diagnosed as having epilepsy, with the cumulative lifetime incidence approaching 3% (Hauser et al., Epilepsia. 1991; 32:429-445; Begley et al., Epilepsia. 1994; 35:1230-1243). The incidence is highest during the first year of life and in elderly persons. Id. 30% to 40% of patients continue to have seizures despite the use of existing antiepileptic drugs either alone or in combination (Kwan et al., N Engl J. Med. 2000; 342:314-319). Patients with uncontrolled seizures experience significant morbidity and mortality and face social stigma and discrimination as well.
Known anti-epileptic drugs include “traditional” medications such as phenobarbital, primidone, phenyloin, carbamazepine, and valproate; as well as newer antiepileptic drugs that induce voltage-dependent ion channel blockade, enhancement of inhibitory neurotransmission, and/or reduction of excitatory neurotransmission. Examples include glutamate antagonism at N-methyl-D-aspartate (NMDA) receptors (e.g., felbamate) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (e.g., felbamate, topiramate) and inhibition of γ-aminobutyric acid (GABA) reuptake in neurons and astrocytes (e.g., tiagabine).
Post synaptic density protein 95 (PSD-95) couples NMDARs to pathways mediating excitotoxicity and ischemic brain damage (Aarts et al., Science 298, 846-850 (2002)). This coupling was disrupted by transducing neurons with peptides that bind to modular domains on either side of the PSD-95/NMDAR interaction complex. This treatment attenuated downstream NMDAR signaling without blocking NMDAR activity, protected cultured cortical neurons from excitotoxic insults and reduced cerebral infarction volume in rats subjected to transient focal cerebral ischemia. This result has led to the proposal to use peptide antagonists of PSD-95/NMDAR for treating stroke and other diseases mediated by excitotoxicity. No significant side effects have been observed in phase I trials of one such antagonist.